Hypercholesterolemia is known to be one of the prime risk factors for atherosclerosis and coronary heart disease, the leading cause of death and disability in western countries. The bile acid sequestrants seem to be moderately effective as antihypercholesterolemic agents but they must be consumed in large quantities, i.e., several grams at a time, and they are not very palatable.
MEVACOR.RTM. (lovastatin), now commercially available, is one of a group of very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase. In addition to the natural fermentation products, mevastatin and lovastatin, there are a variety of semi-synthetic and totally synthetic analogs thereof. For example, simvastatin wherein the 8-acyl moiety is 2,2-dimethylbutyryl is an even more potent HMG-CoA reductase inhibitor than lovastatin.
The naturally occurring compounds and their semi-synthetic analogs have the following general structural formulae: ##STR2## wherein:
Z is hydrogen, C.sub.1-5 alkyl or C.sub.1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino; and
R* is: ##STR3## wherein Q is ##STR4## R.sup.3 is H or OH; M is ##STR5## R.sup.4 is hydrogen or hydroxy; X is CR.sup.5 R.sup.6, O, S, or NH; R.sup.5 and R.sup.6 are H, OH, or OR.sup.7 where R.sup.7 represents a phosphoryl or acyl moiety;
R.sup.2 is hydrogen or methyl; and a, b, c, and d represent single bonds, one of a, b, c or d represents a double bond, or both a and c or both b and d represent double bonds provided that when a is a double bond, Q is ##STR6## and when d is a double bond, M is ##STR7## and provided that when R.sup.5 or R.sup.6 is OH or OR.sup.7 or X is O, S, or NH, a, b, and c are single bonds.
U.S. Pat. No. 4,517,373 discloses semi-synthetic hydroxy containing compounds represented by the above general formula wherein R* is ##STR8##
U.S. Pat. No. 4,537,859 and U.S. Pat. No. 4,448,979 also disclose semi-synthetic hydroxy-containing compounds represented by the above general formula wherein R* is ##STR9##
These compounds are prepared by the action of certain microorganisms on the corresponding non-hydroxylated substrates. One such organism described in U.S. Pat. No. 4,537,859 is of the genus Nocardia.
Copending U.S. patent application Ser. No. 213,010 filed Jun. 29, 1988 discloses 5-oxygenated compounds of the above formula wherein R* is: ##STR10## wherein R.sub.5 and R.sub.6 independently are H, OH or an oxygenated derivative OR.sub.7 provided that one and only one of R.sub.5 and R.sub.6 is OH or OR.sub.7.
Copending U.S. patent application Ser. No. 250,646 filed Sept. 29, 1988 discloses a chemical methodology to the 5-oxygenated compounds described above.
British patent GB No. 2,075,013 discloses compounds of the above formula wherein R* is: ##STR11## wherein A amongst other groups is C.dbd.O, B amongst other groups is --CHOR.sup.3 in which R.sup.3 represents an H or a acyl group, R.sup.1 is an H or a methyl group and R.sup.2 is an H or a acyl group. The 3-keto, 5-hydroxy compound in this disclosure is formed in minor amounts from a chemical oxidation of the hexahydro starting material.